Budesonide Solubility in 2-Propanol+ Water Mixtures at T = (293.2 to 313.2) K: Experimental Measurement, Thermodynamic Analysis and Mathematical Modeling

Document Type : Research Article


1 Department of Health Management and Economics, School of Medicine, AJA University of Medical Sciences, Tehran, I.R. IRAN

2 Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, I.R. IRAN

3 Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, I.R. IRAN


A shake-flask method was used to investigate the solubility and thermodynamic properties of budesonide (BDS) in the temperature scope of 293.2-313.22 K in aqueous mixtures of 2-propanol. There are two categories of mathematical models used to fit the experimental data: linear and non-linear cosolvency mathematical models, such as the van't Hoff's model, Yalkowsky's equation, CNIBS/R–K model, Buchowski, and Ksiazczak equation, modified Wilson model, the Williams-Amidon excess Gibbs energy model, and two Jouyban-Acree models: the Jouyban-Acree and the Jouyban-Acree-van't Hoff. The experimental data for BDS solubility at 298.1 K was also represented with KAT-LSER model. Using back-calculated solubility data, mean relative deviations (MRDs %) of used models were calculated to illustrate fitness and accuracy. Furthermore, van't Hoff and Gibbs equations have been applied to describe how BDS dissolves in binary solvent mixtures with entropy, enthalpy, and Gibbs free energy included.


Main Subjects

[1] Abdalla M.I., Herfarth H., Budesonide for the Treatment of Ulcerative Colitis, Expert Opin. Pharmacother, 17(11): 1549-1559 (2016).
[2] Lichtenstein G.R., Hanauer S.B., Sandborn W.J., Management of Crohn's Disease in Adults, Am. J. Gastroenterol., 104(2): 465-483 (2009).
[3] Kuenzig M.E., Rezaie A., Seow C.H., Otley A.R., Steinhart A.H., Griffiths A.M., Kaplan G.G., Benchimol E.I., Budesonide for Maintenance of Remission in Crohn's Disease, Cochrane Database Syst. Rev., 2014(8): CD002913 (2014).
[4] Johansson S.-Å., Andersson K.-E., Brattsand R., Gruvstad E., Hedner P., Topical and Systemic Glucocorticoid Potencies of Budesonide and Beclomethasone Dipropionate in Man, Eur. J. Clin. Pharmacol., 22(6): 523-529 (1982).
[5] Juniper E.F., Kline P.A., Vanzieleghem M.A., Ramsdale E.H., O'byrne P.M., Hargreave F.E., Effect of Long-Term Treatment with an Inhaled Corticosteroid (Budesonide) on Airway Hyperresponsiveness and Clinical Asthma in Nonsteroid-Dependent Asthmatics, Am. Rev. Respir. Dis., 142(4): 832-836 (1990).
[7] Femere R., Aronson J., Chloroquine and Hydroxychloroquine in Covid-19, BMJ., 2020: 369 (2020).
[8] Khoubnasabjafari M., Jouyban A., Mahdavi A.M., Namvar L., Esalatmanesh K., Hajialilo M., Dastgiri S., Soroush M., Safiri S., Khabbazi A., Prevalence of COVID-19 in Patients with Rheumatoid Arthritis (RA) Already Treated with Hydroxychloroquine (HCQ) Compared with HCQ-Naive Patients with RA: A Multicentre Cross-Sectional Study, Postgrad. Med. J., 98(2): 92-93 (2022).
[9] Huang B., Ling R., Cheng Y., Wen J., Dai Y., Huang W., Characteristics and Therapeutic Options of the Coronavirus Disease 2019, Mol. Ther. Methods Clin. Dev., 18: 367-375 (2020).
[10] Ramakrishnan S., Nicolau D.V., Langford B., Mahdi M., Jeffers H., Mwasuku C., Krassowska K., Fox R., Binnian I., Glover V., Inhaled Budesonide in the Treatment of Early COVID-19 (STOIC): a Phase 2, Open-Label, Randomised Controlled Trial, Lancet Respir. Med., 9(7): 763-772 (2021).
[11] Daley‐Yates P.T., Inhaled Corticosteroids: Potency, dose Equivalence and Therapeutic Index, Br. J. Clin. Pharmacol., 80(3): 372-380 (2015).
[12] Ali H.S., York P., Blagden N., Soltanpour S., Acree Jr W.E., Jouyban A., Solubility of Budesonide, Hydrocortisone, and Prednisolone in Ethanol+ Water Mixtures at 298.2 K, J. Chem. Eng. Data., 55(1): 578-582 (2010).
[13] Bhatt H., Naik B., Dharamsi A., Solubility Enhancement of Budesonide and Statistical Optimization of Coating Variables for Targeted Drug Delivery, Int. J. Pharm., 2014: 262194 (2014).
[17] Di L., Fish P.V., Mano T., Bridging Solubility Between Drug Discovery and Development, Drug Discov. Today., 17(9-10): 486-495 (2012).
[18] Zhou L., Yang L., Tilton S., Wang J., Development of a High Throughput Equilibrium Solubility Assay Using Miniaturized Shake‐Flask Method in Early Drug Discovery, J. Pharm. Sci., 96(11): 3052-3071 (2007).
[19] Mohamadian E., Hamidi S., Martínez F., Jouyban A., Solubility Prediction of Deferiprone in N-Methyl-2-Pyrrolidone+ Ethanol Mixtures at Various Temperatures Using a Minimum Number of Experimental Data, Phys. Chem. Liquids., 55(6): 805-816 (2017).
[20] Rahimpour E., Mohammadian E., Acree Jr W.E., Jouyban A., Computational Tools for Solubility Prediction of Celecoxib in the Binary Solvent Systems, J. Mol. Liq., 299: 112129 (2020).
[21] Khan A.D., Singh L., Various Techniques of Bioavailability Enhancement: A Review, J. Drug Deliv. Ther., 6(3): 34-41 (2016).
[22] Hu Y., Liu Z., Yuan X., Zhang X., Molecular Mechanism for Liquid-Liquid Extraction: Two‐Film Theory Revisited, AIChE Journal., 63(6): 2464-2470 (2017).
[23] Eixarch H., Haltner-Ukomadu E., Beisswenger C., Bock U., Drug Delivery to the Lung: Permeability and Physicochemical Characteristics of Drugs as the Basis for a Pulmonary Biopharmaceutical Classification System (pBCS), J. Epithel. Biol. Pharmacol., 3(1): 1-14 (2010).
[24] Hastedt J.E., Bäckman P., Clark A.R., Doub W., Hickey A., Hochhaus G., Kuehl P.J., Lehr C.-M., Mauser P., McConville J., Scope and Relevance of
a Pulmonary Biopharmaceutical Classification System AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD
, AAPS Open., 2: 1 (2016).
[26] Jouyban-Gharamaleki A., Valaee L., Barzegar-Jalali M., Clark B., Acree Jr W., Comparison of Various Cosolvency Models for Calculating Solute Solubility in Water–Cosolvent Mixtures, Int. J. Pha., 177(1): 93-101 (1999).
[27] Mohammadian E., Foroumadi A., Hasanvand Z., Rahimpour E., Zhao H., Jouyban A., Simulation of Mesalazine Solubility in the Binary Solvents at Various Temperatures, J. Mol. Liq., 357: 119160 (2022).
[28] Mohammadian E., Rahimpour E., Barzegar-Jalali M., Dadmand S., Martinez F., Jouyban A., Solubility of Celecoxib in 1-Propanol+ Water Mixtures at T=(293.2–313.2) K: Experimental Data and Thermodynamic Analysis, Ph. Chem. Liquids., 58(2): 175-183 (2020).
[29] Mohammadian E., Barzegar-Jalali M., Rahimpour E., Solubility Prediction of Lamotrigine in Cosolvency Systems Using Abraham and Hansen Solvation Parameters, J. Mol. Liq., 276: 675-679 (2019).
[30] Hatefi A., Jouyban A., Mohammadian E., Acree Jr W.E., Rahimpour E., Prediction of Paracetamol Solubility in Cosolvency Systems at Different Temperatures, J. Mol. Liq., 273: 282-291 (2019).
[31] Mohammadian E., Jouyban A., Barzegar-Jalali M., Acree Jr W.E., Rahimpour E., Solubilization of Naproxen: Experimental Data and Computational Tools, J. Mol. Liq., 288: 110985 (2019).
[32] Ruidiaz M.M.A., Rodríguez D.S.J., Neita R.P.C., Cristancho B.D.M., Martínez R.F., Performance of the Jouyban-Acree Model for Correlating the Solubility of Indomethacin and Ethylhexyl Triazone in Ethyl Acetate+ Ethanol Mixtures, Vitae., 17(3): 309-316 (2010).
[33] Mohammadian E., Rahimpour E., Martinez F., Jouyban A., Budesonide Solubility in Polyethylene Glycol 400+ Water at Different Temperatures: Experimental Measurement and Mathematical Modelling, J. Mol. Liq., 274: 418-425 (2019).
[34] Barzegar-Jalali M., Rahimpour E., Martinez F., Jouyban A., Determination and Mathematical Modelling of Budesonide Solubility in N-Methyl-2-Pyrrolidone+ Water Mixtures from T= 293.2 to 313.2 K, Phys Chem Liquids., 56(6): 834-842 (2018).
[35] Mohammadian E., Rahimpour E., Martinez F., Jouyban A., Solubility of Budesonide in {Ethanol+ Water} Mixtures from T=(293.2 to 313.2) K: Experimental Measurement and Mathematical Modelling, Phys Chem Liquids., 56(6): 751-758 (2018).
[36] Barzegar-Jalali M., Jouyban A., Mohammadian E., Martinez F., Rahimpour E., Budesonide Solubility in some Non-Aqueous Mono-Solvents at Different Temperatures: Measurements and Mathematical Correlation with Abraham Model, J. Mol. Liq., 269: 461-466 (2018).
[37] Mota F.L., Carneiro A.P., Queimada A.J., Pinho S.P., Macedo E.A., Temperature and Solvent Effects in the Solubility of Some Pharmaceutical Compounds: Measurements and Modeling, Eur. J. Pharm. Sci., 37(3-4): 499-507 (2009).
[38] Acree B., “Toxicity and Drug Testing”, InTech, Kenya (2012).
[39] Wei T., Wang C., Du S., Wu S., Li J., Gong J., Measurement and Correlation of the Solubility of Penicillin V Potassium in Ethanol+ Water and 1-Butyl Alcohol+ Water Systems, J. Chem. Eng. Data, 60(1): 112-117 (2015).
[40] Vahdati S., Shayanfar A., Hanaee J., Martínez F., Acree W.E., Jouyban A., Solubility of Carvedilol in Ethanol+ Propylene Glycol Mixtures at Various Temperatures, Ind. Eng. Chem. Res., 52(47): 16630-16636 (2013).
[41] Perlovich G.L., Kurkov S.V., Bauer-Brandl A., Thermodynamics of Solutions: II. Flurbiprofen and Diflunisal as Models for Studying Solvation of Drug Substances, Eur. J. Pharm. Sci., 19(5): 423-432 (2003).
[42] Zhou C., Shi X., Wang H., An N., Measurement and Correlation of Solubilities of Trans-Ferulic Acid in Solvents, J. Ind. Eng. Chem., 58(11): 2705 (2007).
[43] Gantiva M., Martínez F., Thermodynamic Analysis of the Solubility of Ketoprofen in some Propylene Glycol+ Water Cosolvent Mixtures, Fluid Ph. Equilibria., 293(2): 242-250 (2010).
[45] S.H. Yalkowsky T.J.R., Techniques of Solubilization of Drugs, M. Dekker, New York (1981).
[46] Valvanix S., Yalkowsky S.H., Roseman T., Solubility and Partitioning IV: Aqueous Solubility and Octanol-Water Partition Coefficients of Liquid Nonelectrolytes, J. Pharm. Sci., 70(5): 502-507 (1981).
[49] Sun H., Li M., Jia J., Tang F., Duan E., Measurement and Correlation of the Solubility of 2, 6-Diaminohexanoic Acid Hydrochloride in Aqueous Methanol and Aqueous Ethanol Mixtures, J. Chem. Eng. Data, 57(5): 1463-1467 (2012).
[50]  Jouyban-Gharamaleki A., The modified Wilson Model and Predicting Drug Solubility in Water-Cosolvent Mixtures, Chem. Pharm. Bull., 46(6): 1058-1061 (1998).
[51] Buchowski H., Ksiazczak A., Pietrzyk S., Solvent Activity Along a Saturation Line and Solubility of Hydrogen-Bonding Solids, J. Phys. Chem., 84(9): 975-979 (1980).
[53] Li X., Zhu Y., Zhang X., Farajtabar A., Zhao H., Solubility, Preferential Solvation, and Solvent Effect of Micoflavin in Aqueous Mixtures of Dimethylsulfoxide, Isopropanol, Propylene Glycol, and Ethanol, J. Chem. Eng. Data., 65(4): 1976-1985 (2020).
[55] Jouyban A., Rahimpour E., Karimzadeh Z., A New Correlative Model to Simulate the Solubility of Drugs in Mono-Solvent Systems at Various Temperatures, J. Mol. Liq., 343: 117587 (2021).
[58] Aerts J., “The Hoy Solubility Parameter Calculation Software”, Germany: Computer Chemistry Consultancy, Singen, Germany (2005).
[59] Maitra A., Bagchi S., Study of Solute–Solvent and Solvent–Solvent Interactions in Pure and Mixed Binary Solvents, J. Mol. Liq., 137(1-3): 131-137 (2008).
[60] Islam T., Islam Sarker M.Z., Uddin A.H., Yunus K.B., Prasad R., Mia M.A.R., Ferdosh S., Kamlet Taft Parameters: A Tool to Alternate the Usage of Hazardous Solvent in Pharmaceutical and Chemical Manufacturing/Synthesis-A Gateway Towards Green Technology, Anal. Chem. Lett., 10(5): 550-561 (2020).
[61] Sherwood J., Granelli J., McElroy C.R., Clark J.H., A method of Calculating the Kamlet–Abboud–Taft Solvatochromic Parameters Using COSMO-RS, Molecules, 24(12): 2209 (2019).
[62] Akerlof G., Dielectric Constants of some Organic Solvent-Water Mixtures at Various Temperatures, J. Am. Chem. Soc., 54(11): 4125-4139 (1932).
[64] Rezaei H., Rahimpour E., Martinez F., Zhao H., Jouyban A., Study and Mathematical Modeling of Caffeine Solubility in N-Methyl-2-Pyrrolidone+ Ethylene Glycol Mixture at Different Temperatures, J. Mol. Liq., 341: 117350 (2021).
[65] Li A., Yalkowsky S.H., Predicting Cosolvency. 1. Solubility Ratio and Solute Log K ow, Eng. Chem. Res., 37(11): 4470-4475 (1998).
[66] Jouyban A., Fakhree M., A New Definition of Solubilization Power of a Cosolvent, Int. J. Pharm. Sci., 63(4): 317-318 (2008).
[67] Bevington P.R., Robinson D.K., “Data Reduction and Error Analysis for the Physical Sciences” McGraw-Hill, New York 19692: 235 (1969).
[68] Carstensen J.T., “Modeling and Data Treatment in the Pharmaceutical Sciences”, CRC Press (1996).
[69] Krug R., Hunter W., Grieger R., Enthalpy-Entropy Compensation. 2. Separation of the Chemical from the Statistical Effect, J. Phys. Chem., 80(21): 2341-2351 (1976).
[71] Jouyban-Gharamaleki A., Acree W., Comparison of Models for Describing Multiple Peaks in Solubility Profiles, Int. J. Pharm. 167(1-2): 177-182 (1998).